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- PDB-22ta: 5HT2AR-miniGq heterotrimer in complex with a novel agonist IHCH-8152 -

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Basic information

Entry
Database: PDB / ID: 22ta
Title5HT2AR-miniGq heterotrimer in complex with a novel agonist IHCH-8152
Components
  • 5-hydroxytryptamine receptor 2A
  • Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • single-chain variable fragment 16 (scFv16)
KeywordsMEMBRANE PROTEIN / GPCR / serotonin receptor / 5HT2AR
Function / homology
Function and homology information


positive regulation of heat generation / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / cell body fiber / artery smooth muscle contraction / positive regulation of cytokine production involved in immune response ...positive regulation of heat generation / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / cell body fiber / artery smooth muscle contraction / positive regulation of cytokine production involved in immune response / sensitization / Serotonin receptors / phospholipase C-activating serotonin receptor signaling pathway / G protein-coupled serotonin receptor activity / serotonin receptor signaling pathway / urinary bladder smooth muscle contraction / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / serotonin binding / positive regulation of platelet aggregation / negative regulation of synaptic transmission, glutamatergic / beta-2 adrenergic receptor binding / neurotransmitter receptor activity / positive regulation of DNA biosynthetic process / negative regulation of potassium ion transport / temperature homeostasis / detection of temperature stimulus involved in sensory perception of pain / developmental growth / PKA activation in glucagon signalling / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of vasoconstriction / regulation of dopamine secretion / positive regulation of execution phase of apoptosis / protein tyrosine kinase activator activity / D1 dopamine receptor binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Hedgehog 'off' state / insulin-like growth factor receptor binding / release of sequestered calcium ion into cytosol / behavioral response to cocaine / presynaptic modulation of chemical synaptic transmission / ionotropic glutamate receptor binding / adenylate cyclase activator activity / bone development / dendritic shaft / memory / platelet aggregation / caveola / intracellular calcium ion homeostasis / G-protein beta/gamma-subunit complex binding / positive regulation of neuron apoptotic process / Olfactory Signaling Pathway / Activation of the phototransduction cascade / positive regulation of inflammatory response / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / heterotrimeric G-protein complex / positive regulation of cold-induced thermogenesis / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / cellular response to prostaglandin E stimulus / GPER1 signaling / G alpha (12/13) signalling events / presynapse / Inactivation, recovery and regulation of the phototransduction cascade / G-protein beta-subunit binding / extracellular vesicle / positive regulation of cytosolic calcium ion concentration / Thrombin signalling through proteinase activated receptors (PARs) / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / chemical synaptic transmission / GTPase binding / cytoplasmic vesicle / presynaptic membrane / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit ...5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
: / 5-hydroxytryptamine receptor 2A / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsTang, L. / Cao, M. / Li, H. / Meng, B. / Liu, Z. / Cheng, J. / Wang, S.
Funding support China, 6items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82225045 China
Other governmentMinistry of Science and Technology of China (2020YFA0509600 to S.W.)
National Natural Science Foundation of China (NSFC)22177074 China
National Natural Science Foundation of China (NSFC)22377077 China
Other governmentProgram of Shanghai Academic/Technology Research Leader (22XD1421900 to J.C.)
Other governmentShanghai Municipal Government and ShanghaiTech University (to J.C.)
CitationJournal: Nat Neurosci / Year: 2026
Title: Sustained antidepressant-like effects of psychedelics through 5-HTR-β-arrestin signaling.
Authors: Licong He / Lingjie Tang / Dongmei Cao / Wenwen Duan / Jing Yu / Pei Zhang / Huiqiong Li / Yumeng Wang / Bing Meng / Huan Wang / Yue Zhou / Wenhao Li / Xiaoyu Li / Zhijie Liu / Lei Zhang / ...Authors: Licong He / Lingjie Tang / Dongmei Cao / Wenwen Duan / Jing Yu / Pei Zhang / Huiqiong Li / Yumeng Wang / Bing Meng / Huan Wang / Yue Zhou / Wenhao Li / Xiaoyu Li / Zhijie Liu / Lei Zhang / Jianjun Cheng / Sheng Wang /
Abstract: Psychedelics produce long-lasting antidepressant effects, but their hallucinogenic properties limit clinical use. Using structure-guided design of 5-HTR-β-arrestin-biased agonists, we identified β- ...Psychedelics produce long-lasting antidepressant effects, but their hallucinogenic properties limit clinical use. Using structure-guided design of 5-HTR-β-arrestin-biased agonists, we identified β-arrestin signaling as a critical driver of prolonged antidepressant-like effects in mice. Here we show that the slow-dissociation kinetics of lysergic acid diethylamide (LSD) enable progressive accumulation of 5-HTR engagement during repeated low-dose administration, approaching the receptor occupancy achieved by an acute high dose while avoiding its high peak concentration. This kinetic separation sustains β-arrestin signaling while limiting robust Gα-mediated Ca responses. Consistent with this framework, repeated low-dose LSD and repeated low-dose psilocybin pretreatment followed by a high-dose psychedelic challenge produced sustained antidepressant-like behavioral effects in mice. In parallel, these regimens produced no detectable psychedelic-associated behavioral disruption in mice and cynomolgus macaques. Together, these findings uncover the signaling basis of sustained psychedelic efficacy and provide a rational framework for developing nonhallucinogenic psychedelic therapies for psychiatric disorders.
History
DepositionJan 22, 2026Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Oct 21, 2026Provider: repository / Type: Initial release
Revision 1.0Oct 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2026Group: Data collection / Database references / Category: citation / citation_author / em_admin
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Revision 1.1Nov 4, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / EM metadata / Category: citation / citation_author / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 5-hydroxytryptamine receptor 2A
B: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
D: single-chain variable fragment 16 (scFv16)
hetero molecules


Theoretical massNumber of molelcules
Total (without water)139,2595
Polymers138,9404
Non-polymers3181
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 5-hydroxytryptamine receptor 2A / 5-HT-2 / 5-HT-2A / Serotonin receptor 2A


Mass: 37507.270 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR2A, HTR2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P28223
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / G gamma-I / Adenylate cyclase-stimulating G alpha protein / Extra large alphas protein / XLalphas


Mass: 36558.590 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2, GNAS, GNAS1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P59768, UniProt: Q5JWF2, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37342.785 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: Antibody single-chain variable fragment 16 (scFv16)


Mass: 27531.625 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Chemical ChemComp-A1EEO / ~{N}-(3-azanylcyclobutyl)-2-(4-hexoxyphenyl)-~{N}-methyl-ethanamide


Mass: 318.454 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H30N2O2 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: 5-HT2A receptor bound to IHCH-8152 in complex with a mini-Gq protein and an active-state stabilizing single-chain variable fragment (scFv16) obtained by cryo-electron microscopy (cryoEM)
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil
VitrificationCryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 281 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1000 nm
Image recordingAverage exposure time: 2 sec. / Electron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of real images: 8564

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2PHENIXmodel refinement
13CCP4 package3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 791492 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0048391
ELECTRON MICROSCOPYf_angle_d0.62511429
ELECTRON MICROSCOPYf_dihedral_angle_d5.0221214
ELECTRON MICROSCOPYf_chiral_restr0.0431339
ELECTRON MICROSCOPYf_plane_restr0.0051449

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